Breyanzi DLBCL

Breyanzi DLBCL

Overview of FDA Approval of Breyanzi

Breyanzi was approved by the U.S. FDA on February 5, 2021, for the treatment of adult patients with relapsed or refractory large B-cell lymphoma (r/r LBCL) after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified, high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B.

Specifically, Breyanzi is a CD19-targeted CAR-T therapy developed by Juno Therapeutics, a subsidiary of Bristol Myers Squibb (BMS), and is the third CAR-T gene therapy on the market. In clinical trials, 73% of the 256 evaluable patients achieved an objective response, and 53% achieved a complete remission, with a median time to first response or partial response of approximately 1 month.

Additionally, on June 24, 2022, the FDA further approved the expanded use of Breyanzi, including for the treatment of adult patients with diffuse large B-cell lymphoma (DLBCL) who are refractory to or relapse within 12 months of first-line therapy and are eligible for hematopoietic stem cell transplantation (HSCT). This expanded approval was based on data from the randomized, open-label Phase 3 TRANSFORM study, which evaluated the efficacy and safety of Breyanzi in 184 adults with relapsed or refractory LBCL within 12 months of first-line chemoimmunotherapy.

　　Diffuse Large B-Cell Lymphoma and CAR-T Cell Therapy

Non-Hodgkin’s lymphoma (NHL) is a general term for malignant tumors originating in lymph nodes and lymphoid tissues, clinically presenting mainly as painless, progressive lymphadenopathy or local masses, with systemic and diverse features.

NHL is relatively less common in China, but the incidence has been rising in recent years, accounting for 4% of all new cancers and 90% of all malignant lymphomas.

Based on the origin of the tumor cells, NHL can be classified into different types. Diffuse large B-cell lymphoma (DLBCL) is the most common histological type of NHL, accounting for approximately 31% of NHL cases in foreign countries and 45.8% in China.

CAR-T cell therapy, or chimeric antigen receptor T-cell therapy, involves isolating a patient’s T cells, modifying them with chimeric antigen receptors, and then expanding them ex vivo before reinfusing the modified T cells back into the patient to activate the patient’s immune system to kill tumor cells. CTL019 is a CAR-T cell therapy targeting CD19 and has shown good efficacy in acute lymphoblastic leukemia (ALL).

Studies have found that using CTL019 to treat patients with relapsed/refractory CD19+ lymphoma, the objective response rate for DLBCL reached 54%, and the median progression-free survival (PFS) at a median follow-up of 11.7 months was 43%. Additionally, multiple studies from abroad have shown that CAR-T cell therapy can reduce the risk of relapse and prolong survival in patients with diffuse large B-cell lymphoma.

Significance of Breyanzi for DLBCL Patients

Diffuse large B-cell lymphoma (DLBCL) is a difficult-to-treat aggressive blood cancer, with up to 40% of patients experiencing relapsed or refractory disease after initial treatment. For these patients, the only potential curative approach is intensive salvage immunochemotherapy followed by high-dose chemotherapy and hematopoietic stem cell transplantation (HSCT) for those who respond to salvage therapy.

However, in clinical practice, due to factors such as patient age and comorbidities, approximately half of patients are considered ineligible for HSCT, and it is estimated that only 25% of candidates can undergo stem cell transplantation and obtain long-term clinical benefits. For other patients unable to receive treatment, therapeutic options are limited, and without timely treatment, their expected survival is only 3-4 months.

Breyanzi is a CD19-targeted chimeric antigen receptor (CAR-T) therapy administered as a defined composition to reduce variability in the CD8 and CD4 component doses. Breyanzi contains a 4-1BB costimulatory domain, which can enhance the expansion and persistence of CAR-T cells.

Breyanzi was previously approved by the FDA for the treatment of adult patients with relapsed or refractory LBCL after two or more lines of systemic therapy, including diffuse large B-cell lymphoma (DLBCL) not otherwise specified (including DLBCL arising from indolent lymphoma), high-grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, and follicular lymphoma grade 3B.

Breyanzi Demonstrates Overwhelming Superiority in EFS

The newly approved indication was based on the results of the Phase 3 TRANSFORM trial and the Phase 2 PILOT trial. The Phase 3 TRANSFORM trial enrolled patients aged 18 to 75 years with aggressive non-Hodgkin’s lymphoma, including DLBCL (not otherwise specified), DLBCL with histologic features of high-grade B-cell lymphoma, follicular lymphoma grade 3B, primary mediastinal LBCL, or T-cell/histiocyte-rich LBCL. The primary endpoint was event-free survival (EFS), and secondary endpoints included complete response (CR) rate, progression-free survival (PFS), and overall survival (OS). Other endpoints of interest included duration of response (DOR), objective response rate (ORR), and safety.

At a median follow-up of 6.2 months, researchers compared the primary endpoint and other data between the two treatment groups. In the Breyanzi treatment group (n=92), the median EFS was 10.1 months (95% CI, 6.1–not reached [NR]), while in the standard of care (SOC) treatment group (n=92; HR, 0.349; 95% CI, 0.229-0.530; P<.0001), the median EFS was 2.3 months (95% CI, 2.2-4.3). This represents an overwhelming advantage of 10.1 months versus 2.3 months!

The median PFS in the Breyanzi group was 14.8 months (95% CI, 6.6-NR), while in the SOC group, it was 5.7 months (95% CI, 3.9-9.4) (HR, 0.406; 95% CI, 0.250-0.659; P=0.0001). This means that the progression-free survival of patients receiving Breyanzi treatment was approximately 2.5 times longer than the control group.

Furthermore, the CR rate induced by Breyanzi was 66% (95% CI, 55.7%-75.8%), while the SOC group was 39% (95% CI, 29.1%-49.9%) (P<0.0001). The ORRs in the investigational and control groups were 86% (95% CI, 77.0%-92.3%) and 48% (95% CI, 27.3%-58.5%), respectively.

Although the OS data were not mature at the final trial data cutoff, a numerical trend favoring CAR-T cell therapy was observed. The estimated 6-month OS rates in the investigational and control groups were 91.8% (95% CI, 85.4%-98.2%) and 89.4% (95% CI, 82.9%-96.0%), respectively; at 12 months, these estimated rates were 79.1% (95% CI, 67.1%-91.1%) and 64.2% (95% CI, 50.5%-77.9%), respectively.

Thus, Breyanzi significantly improved event-free survival (EFS), complete response rates (CRs), and progression-free survival (PFS) in this patient population compared to standard salvage chemotherapy followed by high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HSCT). In the Phase 2 PILOT trial, Breyanzi was used as second-line treatment for frail patients with relapsed/refractory LBCL who were ineligible for HSCT. These patients achieved high, durable overall and complete response rates after receiving Breyanzi treatment. The overall response rate was 80%, with the primary endpoint CR rate of 54%, and the median time to CR was 1 month (range: 0.8-6.9 months). The median duration of response was 11.2 months, and the median duration of response for patients achieving CR was not reached.

Favorable Safety Profile of Breyanzi

Breyanzi also demonstrated a favorable safety profile. Researchers identified cytokine release syndrome (CRS) and neurological events (NEs) as the treatment-emergent adverse events (TEAEs) of special interest for Breyanzi. According to the results from the TRANSFORM and PILOT studies, approximately 45% of patients reported CRS of any grade, with 1.3% reporting Grade 3 CRS. The median time to onset and median duration of CRS were both 4 days. The most common manifestations of CRS (≥10%) included fever (94%), hypotension (42%), tachycardia (28%), chills (23%), hypoxia (16%), and headache (12%).

Additionally, 27% of patients reported NEs of any grade, with 7% reporting Grade 3 NEs. The median time to onset of NEs was 8 days, and the median duration was 6 days. The most common neurological toxicities (≥5%) included encephalopathy (20%), tremor (13%), aphasia (8%), headache (6%), dizziness (6%), and delirium (5%).

The safety profile was consistent with previous reports, and no new or increased safety concerns were identified.

CAR-T cell therapy has provided a new opportunity for survival in patients with refractory DLBCL, but this therapy can also cause toxic side effects, such as cytokine release syndrome (CRS), neurotoxicity (NT), and off-tumor recognition. Currently, the challenges for this therapy include reducing toxicity, prolonging disease-free survival, and determining which factors can predict relapse after successful CAR-T cell therapy for DLBCL.